rs1555865385

Positions:

• chr19-41986174-TAGG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_152296.5(ATP1A3):​c.410_412delCCT​(p.Ser137del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP1A3 NM_152296.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.97

Genes affected

ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity AT1A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_152296.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-41986174-TAGG-T is Pathogenic according to our data. Variant chr19-41986174-TAGG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 503717.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.410_412delCCT	p.Ser137del	disruptive_inframe_deletion	5/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.449_451delCCT	p.Ser150del	disruptive_inframe_deletion	5/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.443_445delCCT	p.Ser148del	disruptive_inframe_deletion	5/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.320_322delCCT	p.Ser107del	disruptive_inframe_deletion	5/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.410_412delCCT	p.Ser137del	disruptive_inframe_deletion	5/23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.410_412delCCT		non_coding_transcript_exon_variant	5/25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ATP1A3-associated neurological disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Nov 11, 2021

This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region of the ATP1A3 protein (p.(Ser137del)). The region deleted is highly conserved (100 vertebrates, UCSC), and is located in a transmembrane helical region. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with dystonia-parkinsonism, and has been reported to segregate with disease in eight affected family members from a single family (Royal Melbourne Hospital; PMID: 25359261, described as c.443_445delGAG, p.Ser148del). It has been classified as a variant of uncertain significance and likely pathogenic (ClinVar ID: 503717). Furthermore, two missense variants at the same position (p.Ser137Phe and p.Ser137Tyr) have been identified in cases with alternating hemiplegia of childhood (PMID: 22842232). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Supporting, PM2_Supporting, PM4_Supporting. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2018

The c.410_412delCCT variant in the ATP1A3 gene has been reported previously to segregate in a family with dystonia, with one unaffected family member also reported to harbor the c.410_412delCCT variant suggesting reduced penetrance for this variant (Wilcox et al., 2014). This variant causes an in-frame deletion of codon Serine 137, denoted p.Ser137del. The c.410_412delCCT variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret c.410_412delCCT as a likely pathogenic variant. -

Dystonia 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 09, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has been reported to segregate with disease in a single family affected with dystonia (PMID: 25359261). This variant is also referred to as c.443_445del (p.Ser148del) in the literature. This variant is not present in population databases (ExAC no frequency). This variant, c.410_412delCCT, results in the deletion of 1 amino acid(s) of the ATP1A3 protein (p.Ser137del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555865385; hg19: chr19-42490326;